Psoriasis is a common skin disease that reportedly afflicts as much as 3% of the population. Hyperproliferation of epidermal keratinocytes, excessive scaling of skin and infiltration of immune cells into the dermis and epidermis of affected areas distinguish this disease. Many of the features which characterize psoriatic lesions are also observed in a variety of autoimmune disorders. Like many autoimmune disorders, an underlying genetic component is thought to predispose susceptible individuals to the development of psoriasis.
Psoriatic immunopathology likely results from the activities of cytokines released by activated keratinocytes or leukocytes. Indeed, IL-1, TNF-.alpha. and IL-8 have all been implicated in disease development. The proinflammatory activity of IL-1 and its ability to induce fibroblast proliferation have been suggested to account for the cellular misregulation observed in psoriatic lesions. However, the finding that IL-1 activity in lesional psoriatic skin is actually reduced relative to either normal or uninvolved psoriatic skin argues for a different mechanism. Thus, the initiating factor responsible for the development of psoriasis may be more complex than the simple misregulation of a cytokine.
Successful management of psoriasis frequently involves the administration of immunosuppressants. Drugs used in the treatment of psoriasis include cyclosporin A, corticosteroids, methotrexate, vitamin D3, vitamin D3 analogs and retinoids. These latter compounds, for example, can both decrease keratinocyte IL-1 production and modulate the interaction between antigen presenting cells and T lymphocytes.
A topically administered synthetic retinoid has recently been shown to dramatically improve the symptoms of psoriasis. More specifically, AGN-190168 (tazarotene/ethyl 6-[2-(4,4) dimethyl-thiochroman-6-yl] ethynyl-nicotinate) is an RAR .beta./.gamma. selective synthetic retinoid that has been proven effective for psoriasis treatment in phase III clinical trials.
Retinoids are the compounds comprising vitamin A and its derivatives. These chemicals play important roles in a variety of biological phenomena including: vision, hematopoiesis, bone development and pattern formation during embryogenesis. Retinoids additionally possess strong antiproliferative activities.
Retinoids exert their biological activities by binding and activating receptors that are transcription factors. These receptors are presently divided into two groups based on their ligand binding specificities. All-trans-RA (RA) binds and activates a class of retinoic acid receptors that includes RAR-.alpha., RAR-.beta. and RAR-.gamma.. A different ligand, 9-cis-RA (9C-RA), binds and activates both the RARs and members of the retinoid X receptor (RXR) family. The RXR family of receptors includes RXR-.alpha., RXR-.beta. and RXR-.gamma.. Thus, at least one class of retinoids exclusively binds and activates the RAR-.alpha., RAR-.beta. and RAR-.gamma. receptors. This selectivity illustrates one mechanism that underlies the specificity of retinoid activity.
The number of retinoid responsive genes identified to date is very limited. Two of these genes encode cellular retinoic acid (RA) binding proteins (CRABP I and CRABP II). The CRABP I and II proteins are highly conserved across species, but are not strongly related to each other. Herein we disclose the discovery and utility of a novel retinoid induced polynucleotide.